Substituted N-[ω-(1H-imidazol-1-yl)alkyl]-amides

ABSTRACT

This disclosure describes novel N-[ω-(1H-imidazol-1-yl)alkyl]amides which possess the property of inhibiting the enzyme thromboxane synthetase.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of our copending applicationSer. No. 482,388, filed Apr. 6, 1983, now abandoned.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds and, more particularly,is concerned with novel substituted N-[ω-(1H-imidazol-1-yl)alkyl]amideswhich may be represented by the following structural formula: ##STR1##wherein A is a divalent moiety of the formulae:

    --C.sub.n H.sub.2n -- or --CH.sub.2 CH═CHCH.sub.2 --

wherein n is an integer from 2 to 8, inclusive; R₁ is hydrogen, alkylhaving from one to three carbon atoms or benzyl; R₂ and R₃ may be thesame or different and are each hydrogen, alkyl having from one to threecarbon atoms or phenyl; Q is a divalent moiety of the formulae: ##STR2##wherein m is zero, 1, 2 or 3; and HET is a heterocyclic moiety of theformulae: ##STR3## wherein Y is oxo (--O--) or thio (--S--); R₄ ishydrogen, halogen, dihalogen, lower alkyl or nitro; and R₅ is hydrogenor halogen. Suitable lower alkyl groups are those having up to threecarbon atoms whereas halogen is exemplified by fluoro, chloro and bromo.

The organic bases of this invention form non-toxic acid-addition saltswith a variety of pharmacologically acceptable organic and inorganicsalt-forming reagents. Thus, acid-addition salts, formed by admixture ofthe organic free base with one or more equivalents of an acid, suitablyin a neutral solvent, are formed with such acids as sulfuric,phosphoric, hydrochloric, hydrobromic, sulfamic, maleic, lactic, malic,succinic, tartaric, acetic, fumaric, gluconic, ascorbic, and the like.For purposes of this invention the free bases are equivalent to theirnon-toxic acid-addition salts. The acid-addition salts of the organicbases of the present invention are, in general, crystalline solids,relatively soluble in water, methanol and ethanol but relativelyinsoluble in non-polar organic solvents such as diethyl ether, benzene,toluene, and the like.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention may be readily prepared asset forth in the following reaction schemes wherein A, R₁, R₂, R₃, Q andHET are as hereinbefore defined; R₆ is alkyl having from one to threecarbon atoms or benzyl; and X is chloro, bromo or a moiety of theformula: ##STR4## wherein Q and HET are as hereinabove defined and theresulting anhydride is symmetrical.

METHOD I ##STR5##

In accordance with Method I, an appropriately substituted acid (1) isreacted with 1,1'-carbonyldiimidazole in an inert solvent such asdioxane, dimethylformamide or tetrahydrofuran at ambient temperaturesfor 1-3 hours to provide the intermediates (2). Treatment of theintermediates (2) with an appropriately substituted1H-imidazole-1-alkanamine (3), either as the free base or a saltthereof, provides the final products (4). The final condensation of(2)+(3) is best carried out by merely adding (3) to the reaction mixturecontaining (2) and then heating at the reflux temperature for 1-5 hours.Concentration of the reaction mixture followed by the addition ofaqueous base (KOH or NaOH) in a solvent such as CHCl₃ or CCl₄ andisolation from the organic phase provides the products (4) as the freebases.

METHOD II ##STR6##

In accordance with Method II, an appropriately substituted acid halideor acid anhydride (5) is condensed with an appropriately substituted1H-imidazole-1-alkanamine (3), either as the free base or a saltthereof, to provide the final products (4). This condensation is bestcarried out at ambient temperatures for up to 18 hours in an inertsolvent such as CH₂ Cl₂, CHCl₃ or CCl₄ and in the presence of an acidacceptor such as aqueous base (2N KOH or 2N NaOH), soda ash orconcentrated (12%) aqueous ammonia. The resulting organic phase is thenwashed with water, dried, and concentrated to give the crystallineproducts (4) as the free bases.

METHOD III ##STR7##

In accordance with Method III, an appropriately substitutedN-[w-(1H-imidazol-1-yl)alkyl]amide (6) is treated with sodium hydride inan inert solvent such as dioxane, dimethylformamide or tetrahydrofuranat ambient temperature for 1-3 hours to form the intermediate sodiumsalt in situ. Addition to the reaction mixture of an alkyl halide of theformula: R₆ --Hal (wherein Hal is chloro, bromo or iodo), followed bystirring at ambient temperatures for 12-24 hours provides the alkylatedderivative (7). Isolation of (7) is readily accomplished byconcentration of the reaction mixture, dilution with water, andextraction into a water insoluble solvent such as CH₂ Cl₂, CHCl₃ orCCl₄.

The compounds of this invention inhibit thromboxane synthetase enzyme.Thus, these compounds are useful in the treatment of diseasescharacterized by an imbalance of thromboxane A₂ /prostacyclin such asischemic heart disease, transient ischemic attack, thrombosis andmigraine. Recent reviews have established the role of thethromboxane/prostacyclin balance in the vascular system [(CardiovascularDiseases: New Trends in Surgical and Medical Aspects, H. Barnett, P.Paoletti, E. Flamm and G. Brambilla, eds., Elsevier/North-HollandBiomedical Press, pp 137-150 (1981)]. Prostacyclin (PGI₂) is a potentvasodilator and platelet aggregation inhibitor, whereas thromboxane(TXA₂) is a powerful vasoconstrictor and causative of plateletaggregation. TXA₂ is synthesized by thromboxane synthetase enzymelocated in, for example, blood platelets. When TXA₂ production isincreased relative to PGI₂, platelet aggregation, thrombosis andvasospasm may occur [Lancet (i), 1216 (1977); Lancet, 479 (1977);Science, 1135 (1976); Amer. J. Cardiology, 41, 787 (1978)]. TXA₂synthetase inhibitors have been shown to have superior anti-thromboticaction to that of aspirin [J. Clin. Invest., 65, 400 (1980); Br. J.Pharmac., 76, 3 (1982)].

The role of prostaglandins including TXA₂ and PGI₂ in ischemic heartpatients has been reviewed [Cardiovascular Pharmacology of theProstaglandins, A. G. Herman, P. M. Vanhoute, H. Denolin and A. Goosens,eds., Raven Press, New York, pp 361-374 (1982)]. Injection of TXA₂ intocoronary arteries of guinea pigs and rabbits causes myocardial ischemiaand subendocardial necrosis [Drugs of the Future, 7, 331 (1982); Proc.Jap. Acad., 53(B), 38 (1977); Eur. J. Pharmacol., 53 49(1978)]. Recentresearch has demonstrated the beneficial effects of PGI₂ and selectiveinhibition of thromboxane synthetase on ischemic myocardium in canines[J. Cardiovascular Pharmacology, 4, 129 (1982)]. Thus compounds whichselectively inhibit thromboxane synthetase (and hence TXA₂) withoutadversely affecting PGI₂ are useful in the treatment of vasculardiseases such as ischemia and migraine. In addition, inhibition of TXA₂formation may effectively treat platelet aggregation and preventthrombosis.

Under urethan anesthesia, 10 μl. of arterial blood was collected in oneml. of 3.2% sodium citrate in a polystyrene tube from Okamoto-Aokispontaneously hypertensive rats (SHR) (Taconic Farms, Germantown, NY)between 19 and 24 weeks in age. The blood was diluted with 3 ml. coldsaline and centrifuged at room temperature for 15 minutes at 460×g. Theplatelet rich plasma (PRP) was separated. The platelets were isolated bycentrifuging the PRP for 10 minutes at 1060×g and were washed in 4 ml.cold oxygenated Krebs phosphate buffer, pH 7.4. The chilled plateletsrecovered from centrifuging at 800×g for 10 minutes were resuspended inoxygenated Krebs phosphate buffer and diluted to contain 4.5-6.0×10⁴platelts/μl.

The inhibition of thromboxane (TX) formation was studied by determingthe concentration of thromboxane B₂ (TXB₂), the stable hydrolysisproduct of TXA₂. Assay samples, prepared on ice, contained 200 μl.platelet suspension, 50 μl. saline, and 50 μl. vehicle or drug understudy (OKY-1581, UK-37248-01, 1-benzylimidazole, or indomethacin). Thesamples were incubated for 10 minutes at 37° C. in a metabolic shaker.The reaction was terminated by immersing the tubes in an ice bath andadding 50 μl. of 0.5M citric acid. The samples were centrifuged for 10minutes in a refrigerated centrifuge and the supernatants thus obtainedwere decanted and stored at -20° C. The TXB₂ content for each sample wasdetermined by a direct radio-immunoassay (RIA) utilizing a TXB₂ specificRIA kit purchased from New England Nuclear, Boston, MA and expressed aspg TXB₂ formed minute⁻¹ sample⁻¹, from which the percent inhibition ofTXB₂ formation was calculated. The results of this test onrepresentative compounds of this invention appear in Table I

                  TABLE I                                                         ______________________________________                                        Compound             Dose    % Inhibition                                     ______________________________________                                        N--[3-(1H--imidazol-1-yl)propyl]-2-                                                                10.sup.-4 M                                                                           97                                               furanecarboxamide                                                             3-chloro-N--[3-(1H--imidazol-1-yl)-                                                                10.sup.-4 M                                                                           100                                              propyl]benzo[b]thiophene-2-carbox-                                            amide                                                                         3-chloro-6-fluoro-N--[3-(1H--imida-                                                                10.sup.-4 M                                                                           96                                               zol-1-yl)propyl]benzo[b]thiophene-                                            2-carboxamide                                                                 3-chloro-N--[3-(1H--imidazol-1-yl)-                                                                10.sup.-4 M                                                                           96                                               propyl]-6-methyl-benzo[b]thiophene-                                           2-carboxamide                                                                 N--[3-(1H--imidazol-1-yl)propyl]-3-                                                                10.sup.-4 M                                                                           78                                               furanecarboxamide                                                             5-bromo-N--[3-(1H--imidazol-1-yl)pro-                                                              10.sup.-4 M                                                                           82                                               pyl]-2-furanecarboxamide                                                      N--[3-(1H--imidazol-1-yl)propyl]-2-                                                                10.sup.-4 M                                                                           93                                               thiophenecarboxamide                                                          N--[3-(1H--imidazol-1-yl)propyl]-5-                                                                10.sup.-4 M                                                                           96                                               methyl-2-thiophenecarboxamide                                                 4,5-dibromo-N--[3-(1H--imidazol-1-                                                                 10.sup.-4 M                                                                           100                                              yl)propyl]-2-thiophenecarboxamide                                             N--[3-(1H--imidazol-1-yl)propyl]-2-                                                                10.sup.-4 M                                                                           97                                               benzofuranecarboxamide                                                        5-chloro-N--[3-(1H--imidazol-1-yl)-                                                                10.sup.-4 M                                                                           100                                              propyl]benzo[b]thiophene-2-carboxa-                                           mide                                                                          N--[3-(1H--imidazol-1-yl)propyl]-3-                                                                10.sup.-4 M                                                                           78                                               (2-furanyl)-2-propenamide                                                     N--[3-(1H--imidazol-1-yl)propyl]-3-                                                                10.sup.-4 M                                                                           100                                              (2-thienyl)-2-propenamide                                                     N--[3-(1H--imidazol-1-yl)propyl-5-                                                                 10.sup.-4 M                                                                           64                                               nitro-2-furanecarboxamide                                                     N--[3-(1H--imidazol-1-yl)propyl]-α-                                                          10.sup.-4 M                                                                           73                                               oxo-thiophene acetamide                                                       3-chloro-N--[2-(1H--imidazol-1-yl)-                                                                10.sup.-4 M                                                                           70                                               ethyl]benzo[b]thiophene-2-carboxa-                                            mide                                                                          3-chloro-N--[3-(2-ethyl-1H--imidaz-                                                                10.sup.-4 M                                                                           55                                               ol-1-yl)propyl]benzo[b]thiophene-                                             2-carboxamide                                                                 3-chloro-N--[3-(4-methyl-1H--imidaz-                                                               10.sup.-4 M                                                                           98                                               ol-1-yl)propyl]benzo[b]thiophene-2-                                           carboxamide                                                                   N--[4-(1H--imidazol-1-yl)butyl]-2-                                                                 10.sup.-4 M                                                                           87                                               furanecarboxamide                                                             3-chloro-N--[4-(1H--imidazol-1-yl)-                                                                10.sup.-4 M                                                                           91                                               butyl]benzo[b]thiophene-2-carboxa-                                            mide                                                                          N--[4-(1H--imidazol-1-yl)butyl]thio-                                                               10.sup.-4 M                                                                           95                                               phene-2-carboxamide                                                           5-chloro-N--[3-(1H--imidazole-1-yl)-                                                               10.sup.-4 M                                                                           95                                               propyl]thiophene-2-carboxamide                                                N--[3-(4-methyl-1H--imidazol-1-yl)-                                                                10.sup.-4 M                                                                           51                                               propyl]thiophene-2-carboxamide                                                ______________________________________                                    

The novel compounds of the present invention are also active hypotensiveagents and were tested for hypotensive activity by the method of P. S.Chan and D. Poorvin, Clinical and Experimental Hypertension, 1 (6),817-830 (1979). Male, 16 week old, spontaneously hypertensive rats ofthe Okamoto strain, from Taconic Farms, Germantown, N.Y. having anaverage mean arterial blood pressure of 160±1.5 mm of mercury are usedin the test. One to 3 rats are used per test compound. A rat is dosed bygavage with a test compound, suspended in 2% pre-boiled starch at aconcentration of 50 mg/ml, at a dose of 100 mg/kg of body weight orless, with 0.9% sodium chloride loading at a dose 25 ml/kg of bodyweight. A second identical dose of the test compound, without sodiumchloride loading is given 24 hours later. At 28 hours after the initialdose, the mean arterial blood pressure (MABP) is measured by the methodof Chan and Poorvin vide supra. The procedure is repeated in a secondand third rat when necessary. Based on the data obtained and using thethree-stage "sequential probability ratio test" statistical method, thecritieria for activity or retest are as follows:

If the blood pressure in the first rat is ≦116 mm mercury the compoundis considered active. If the blood pressure is between 117 and 146 mm, asecond rat is used. If the average blood pressure of the first andsecond rats is ≦122 mm the compound is considered active. If the averageblood pressure is between 123 and 137 mm, a third rat is used. If theaverage blood pressure of the three rats is ≦128 mm the compound isconsidered active. The results of this test on representative compoundsof the present invention appear in Table II below.

                  TABLE II                                                        ______________________________________                                                               MABP/mm Hg                                             Compound               (no. of rats)                                          ______________________________________                                        N--[3-(1H--imidazol-1-yl)propyl]-3-furane-                                                           128 (3)                                                carboxamide                                                                   N--[3-(1H--imidazol-1-yl)propyl-5-nitro-2-                                                           114 (3)                                                furanecarboxamide                                                             N--[3-(1H--imidazol-1-yl)propyl]-60 -oxo-                                                            125 (3)                                                thiophene acetamide                                                           3-chloro-N--[2-(1H--imidazol-1-yl)ethyl]-                                                            117 (3)                                                benzo[b]thiophene-2-carboxamide                                               N--[4-(1H--imidazol-1-yl)butyl]thiophene-                                                            114 (2)                                                2-carboxamide                                                                 5-chloro-N--[3-(1H--imidazol-1-yl)propyl]-                                                           125 (3)                                                thiophene-2-carboxamide                                                       5-chloro-N--[4-(1H--imidazol-1-yl)butyl]-                                                            118 (2)                                                thiophene-2-carboxamide                                                       N--[3-(1H--imidazol-1-yl)propyl]thiophene-                                                           121 (2)                                                2-butanamide                                                                  ______________________________________                                    

The novel compounds of the present invention have been found to behighly useful for inhibiting thromboxane synthetase in mammals whenadministered in amounts ranging from about 0.1 mg. to about 20.0 mg/kgof body weight per day. A preferred dosage regimen for optimum resultswould be from about 0.5 mg. to about 10.0 mg/kg of body weight per day.Such dosage units are employed that a total of from about 35 to about700 mg. of active compound for a subject of about 70 kg. of body weightare administered in a 24 hour period. This dosage regimen may beadjusted to provide the optimum therapeutic response. For example,several divided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation. The compounds of this invention are preferably administeredorally but may be administered in any convenient manner such as by theintravenous, intramuscular, or subcutaneous routes.

Compositions according to the present invention having the desiredclarity, stability and adaptability for parenteral use are obtained bydissolving from 0.10% to 10.0% by weight of active compound in a vehicleconsisting of a polyhydric aliphatic alcohol or mixtures thereof.Especially satisfactory are glycerin, propylene glycol, and polyethyleneglycols. The polyethylene glycols consist of a mixture of non-volatile,normally liquid, polyethylene glycols which are soluble in both waterand organic liquids and which have molecular weight of from about 200 to1500. Although the amount of active compound dissolved in the abovevehicle may vary from 0.10% to 10.0% by weight, it is preferred that theamount of active compound employed be from about 3.0 to about 9.0% byweight. Although various mixtures of the aforementioned non-volatilepolyethylene glycols may be employed, it is preferred to use a mixturehaving an average molecular weight of from about 200 to about 400.

In addition to the active compound, the parenteral solutions may alsocontain various preservatives which may be used to prevent bacterial andfungal contamination. The preservatives which may be used for thesepurposes are, for example, myristyl-gamma-picolinium chloride,benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-α-glycerolether, methyl and propyl parabens, and thimerosal. As a practicalmatter, it is also convenient to employ antioxidants. Suitableantioxidants include, for example, sodium bisulfite, sodiummetabisulfite, and sodium formaldehyde sulfoxylate. Generally, fromabout 0.05 to about 0.2% concentration of antioxidant are employed.

For intramuscular injection, the preferred concentration of activecompound is 0.25 to 0.50 mg/ml of the finished compositions. The novelcompounds of the present invention are equally adapted to intravenousadministration when diluted with water or diluents employed inintravenous therapy such as isotonic glucose in appropriate quantities.For intravenous use, intital concentrations down to about 0.05 to 0.25mg/ml of active ingredient are satisfactory.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compounds may be incorporated with excipientsand used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, waters, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2% to about 60% of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills, or capsules maybe coated with shellac, sugar or both. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orangeflavor. Of course, any material used in preparing any dosage unit formshould be pharmaceutically pure and substantially non-toxic in theamounts employed.

The following specific examples illustrate the preparation of thecompounds of the present invention.

EXAMPLE 1 N-[3-(1H-Imidazol-1-yl)propyl]-2-furanecarboxamide

Following the procedure of Schwan, J. Het. Chem. 4, 633 (1967), 25 ml.of acrylonitrile was heated to 70° C. A 13.6 g. portion of imidazole wasadded and the mixture was gradually heated to 90°-100° C. and maintainedat that temperature for 3 hours. The mixture was then concentrated invacuo to remove excess acrylonitrile, taken up in methanol andreconcentrated. The concentrate was added to 150 ml. of methanol, 100ml. of concentrated ammonium hydroxide and 8 g. of Raney nickel catalystin a Parr apparatus and subjected to hydrogenation at an initialpressure of 53 psi. After approximately 6 hours and the uptake of 32psi. of hydrogen, the mixture was filtered. The filtrate wasconcentrated to remove the solvent, then concentrated once from ethanol,giving 1H-imidazole-1-propanamine as an oil. When this was added to 250ml. of methanolic hydrogen chloride, concentrated to remove the solvent,boiled with 100 ml. of ethanol and then refrigerated, 20.3 g. of1H-imidazole-1-propanamine dihydrochloride was obtained as a tan solid,m.p. 146°-150° C.

A mixture of 1.98 g. of 1H-imidazole-1-propanamine dihydrochloride and30 ml. of 1N sodium hydroxide was stirred at room temperature. A mixtureof 0.98 ml. of 2-furanyl chloride and 50 ml. of dichloromethane wasadded and stirring was continued overnight. More dichloromethane wasadded, the organic layer was separated, washed twice with water andconcentrated, giving 1.0 g. of the desired product, m.p. 111°-113° C.

Following the procedure of this example but using1H-imidazole-1-propanamine dihydrochloride and the indicated acidchlorides, the products of Examples 2-4, listed in Table III, wereobtained.

                  TABLE III                                                       ______________________________________                                        Ex.  Acid Chloride   Product        m.p. °C.                           ______________________________________                                        2    3-chloro-benzo[b]thio-                                                                        3-chloro-N--[3-(1H--                                                                         133-135                                        phene-2-carbonyl chlo-                                                                        imidazol-1-yl)pro-                                            ride            pyl]benzo[b]thio-                                                             phene-2-carboxamide                                      3    3-chloro-6-fluoro-ben-                                                                        3-chloro-6-fluoro-N--                                                                        127-129                                        zo[b]thiophene-2-car-                                                                         [3-(1H--imidazol-1-                                           bonyl chloride  yl)propyl]benzo[b]-                                                           thiophene-2-carbox-                                                           amide                                                    4    3-chloro-6-methyl-ben-                                                                        3-chloro-N--[3-(1H--                                                                         122-125                                        zo[b]thiophene-2-car-                                                                         imidazol-1-yl)pro-                                            bonyl chloride  pyl]-6-methyl-ben-                                                            zo[b]thiophene-2-                                                             carboxamide                                              ______________________________________                                    

EXAMPLE 5 N-[3-(1H-Imidazol-1-yl)propyl]-3-furanecarboxamide

A solution of 2.24 g. of furoic acid, 3.24 g. ofN,N'-carbonyldiimidazole and 80 ml. of tetrahydrofuran was allowed tostir at room temperature for 2 hours. A 4.0 g. portion of1H-imidazole-1-propanamine dihydrochloride was added and the mixture wasstirred at room temperature overnight. The mixture was then heated for 5hours, 5 ml. of water was added, heating resumed for 30 minutes and thenthe mixture was concentrated to remove most of the solvent.Dichloromethane and 60 ml. of 1N sodium hydroxide were added, theorganic layer was separated, washed twice with water, dried andconcentrated, giving 2.0 g. of the desired product, m.p. 127°-129° C.

The fumarate salt of this and the other products of this invention maybe prepared by warming a mixture of one mole of the product (e.g.,N-[3-(1H-imidazol-1-yl)propyl]-2-thiopheneacetamide), one mole offumaric acid and ethanol to solution and then diluting with ether. Theresulting crystals are collected, washed with ether and dried.

Following the procedure of this example but using1H-imidazole-1-propanamine dihydrochloride and the indicated acids (andoptionally converting to the fumarate salt), the products of Examples6-19, listed in Table IV, were obtained.

                  TABLE IV                                                        ______________________________________                                        Ex.  Acid        Product            m.p. °C.                           ______________________________________                                        6    5-bromo-2-  5-bromo-N--[3-(1H--imidazol-                                                                     139-142                                        furoic acid 1-yl)propyl]-2-furanecar-                                                     boxamide                                                     7    2-thiophene N--[3-(1H--imidazol-1-yl)-                                                                       135-137                                        carboxylic  propyl]-2-thiophenecar-                                           acid        boxamide                                                     8    5-methyl-2- N--[3-(1H--imidazol-1-yl)-                                                                       120-122                                        thiophene   propyl]-5-methyl-2-thio-                                          carboxylic  phenecarboxamide                                                  acid                                                                     9    4,5-dibromo-                                                                              4,5-dibromo-N--[3-(1H--imi-                                                                      126-128                                        2-thiophene dazol-1-yl) propyl]-2-                                            carboxylic  thiophenecarboxamide                                              acid                                                                     10   coumarilic  N--[3-(1H--imidazol-1-yl)-                                                                       105-107                                        acid        propyl]-2-benzofurane-                                                        carboxamide                                                  11   5-chloro-ben-                                                                             5-chloro-N--[3-(1H--imidi-                                                                       155-157                                        zo[b]thio-  dazol-1-yl)propyl]benzo-                                          phene-2-car-                                                                              [b]thiophene-2-carboxamide                                        boxylic acid                                                             12   2-thiophene N--[3-(1H--imida-  85-87                                          acetic acid zol-1-yl)propyl]-                                                             2-thiophene -       tamide, fumarate                         13   3-thiophene N--[3-(1H--imidazol-                                                                             84-86                                          acetic acid 1-yl)proyl]-3-                                                                thiopheneaceta-                                                               mide, fumarate                                               14   3-(2-furoyl)                                                                              N--[3-(1H--imida-  77-80                                          acrylic acid                                                                              zol-1-yl)propyl]-                                                             3-(2-furanyl)-2-                                                              propenamide                                                  15   3-(2-thienyl)                                                                             N--[3-(1H--imidazol-                                                                             70-80                                          acrylic acid                                                                              1-yl)propyl]-3-                                                               (2-thienyl)-2-                                                                propenamide                                                  16   5-nitro-2-furoic                                                                           N--[3-(1H--imidazol-                                                                            151-153                                        acid        1-yl)propyl-5-ni-                                                             tro-2-furanecar-                                                              boxamide                                                     17   4-(2-thienyl)                                                                             N--[3-(1H--imidazol-                                                                             oil                                            butyric acid                                                                              1-yl)propyl]-2-                                                               thiophenebutyra-                                                              mide                                                         18   2-thiophene N--[3-(1H--imidazol-                                                                             88-90                                          glyoxylic acid                                                                            1-yl)propyl]-α-                                                         oxo-thiophene                                                                 acetamide                                                    19   5-chloro-2-thio                                                                           5-chloro-N--[3-(1H--                                                                             144-147                                        phene carbo-                                                                              imidazol-1-yl)pro-                                                xylic acid  pyl]thiophene-2-                                                              carboxamide                                                  ______________________________________                                    

EXAMPLE 203-Chloro-N-[2-(1H-imidazol-1-yl)ethyl]benzo[b]thiophene-2-carboxamide

A mixture of 18.0 g. of sodium imidazole, 50.8 g. ofN-(2-bromoethyl)phthalimide and 300 ml. of toluene was refluxed for 24hours. Most of the toluene was decanted and concentrated to remove thesolvents. The residue was refrigerated overnight, then filtered andwashed with diethyl ether. The solid was dissolved in 14 ml. ofisopropanol and cooled, giving 9.2 g. of2-[2-(1H-imidazol-1-yl)ethyl]-isoindole-1,3(2H)-dione.

A mixture of 8.0 g. of2-[2-(1H-imidazol-1-yl)-ethyl]-isoindole-1,3(2H)-dione, 1.75 ml. ofhydrazine hydrate and 120 ml. of ethanol was stirred and refluxed and 3hours, then cooled and 165 ml. of 10% hydrochloric acid was added.Refluxing was continued for one hour, then the mixture was concentratedto dryness, stirred with 135 ml. of 10% hydrochloric acid and filtered.The aqueous layer was concentrated to dryness, boiled with 170 ml. ofethanol and the white solid collected, giving 4.3 g. of1H-imidazole-1-ethanamine dihydrochloride.

A 1.47 g. portion of 1H-imidazole-1-ethanamine dihydrochloride wasreacted with 3-chloro-benzo[b]thiophene-2-carbonyl chloride as describedin Example 1, giving 0.75 g. of the desired product, m.p. 132°-134° C.

In like manner, the reaction of 1H-imidazole-1-ethaneaminedihydrochloride with 2-furoyl chloride by the procedure of Example 1provided N-[2-(1H-imidazol-1-yl)ethyl]-2-furanecarboxamide, m.p.131°-133° C.

Following the procedure of this example, N-(3-bromopropyl)phthalimidewith 4-methylimidazole and 2-ethylimidazole were used to producerespectively2-[3-(4-methyl-1H-imidazol-1-yl)propyl]isoindole-1,3-(2H)-dione and2-[3-(2-ethyl-1H-imidazol-1-yl)-propyl]isoindole-1,3(2H)-dione whichagain following the procedure of this example were convertedrespectively to (4-methyl-1H-imidazol-1-yl)-1-propanaminedihydrochloride and (2-ethyl-1H-imidazol-1-yl)-1-propanaminedihydrochloride which were then converted by the procedure of Example 1,using the appropriate acid chloride, to the products of Examples 21-27,listed in Table V.

                  TABLE V                                                         ______________________________________                                        Ex.  Acid Chloride Product          m.p. °C.                           ______________________________________                                        21   2-furanyl chloride                                                                          N--[3-(2-ethyl-1H--imida-                                                                      81-83                                                        zol-1-yl)propyl]-2-fur-                                                       anecarboxamide                                             22   3-chloro-benzo[b]-                                                                          3-chloro-N--[3-(2-ethyl-                                                                       120-122                                        thiophene-2-carbon-                                                                         1H--imidazol-1-yl-pro-                                          yl chloride   pyl]-benzo[b]thiophene-                                                       2-carboxamide                                              23   2-furanyl chloride                                                                          N--[3-(4-methyl-1H--imida-                                                                     oil                                                          zol-1-yl)propyl]-2-fur-                                                       anecarboxamide                                             24   3-chloro-benzo[b]-                                                                          3-chloro-N--[3-(4-methyl-                                                                      120-135                                        thiophene-2-carbon-                                                                         1H--imidazol-1-yl)pro-                                          yl chloride   pyl]benzo[b]thiophene-2-                                                      carboxamide                                                25   2-thenoyl chloride                                                                          N--[3-(4-methyl-1H--imida-                                                    zol-1-yl)propyl]thio-                                                         phene-2-carboxamide                                        26   4-chloro-2-thenoyl                                                                          4-chloro-N--[3-(4-methyl-                                       chloride      1H--imidazol-1-yl)pro-                                                        pyl]-thiophene-2-car-                                                         boxamide                                                   27   4-chloro-2-thenoyl                                                                          4-chloro-N--[3-(2-ethyl-                                        chloride      1H--imidazol-1-yl)propyl]-                                                    thiophene-2-carboxa-                                                          mide                                                       ______________________________________                                    

EXAMPLE 28 N-[4-(1H-Imidazol-1-yl)butyl]-2-furanecarboxamide

A mixture of 6.3 g. of sodium imidazole, 100 ml. of dimethylformamideand 19.7 g. of N-(4-bromobutyl)-phthalimide was heated on a steam bathfor 6 hours and then concentrated to remove volatile material. Theresidue was boiled with 150 ml. of toluene and the toluene layer wasdecanted and concentrated. The residue was triturated with diethyl etherand cooled, giving N-[4-(1H-imidazol-1-yl)butyl]-isoindole-1,3(2H)-dione(m.p. 75°-77° C.) which was recovered by filtration.

A mixture of 10.0 g. ofN-[4-(1H-imidazol-1-yl)-butyl]isoindole-1,3(2H)-dione, 1.97 ml. ofhydrazine hydrate and 100 ml. of ethanol was heated at reflux for 3hours and then cooled. A 160 ml. of portion of 3N hydrochloric acid wasadded, the mixture was heated at reflux for one hour and thenconcentrated. The residue was stirred with 150 ml. of 3N hydrochloricacid and then filtered. The mother liquor was concentrated to dryness,diluted with 10 ml. of ethanol and cooled, giving1H-imidazole-1-butanamine dihydrochloride (m.p. 132°-146° C.) which wasrecovered by filtration.

When the above procedure is carried out substituting the appropriateN-(bromoalkyl)phthalimide for N-(4-bromo-butyl)phthalimide;1H-imidazole-1-pentanamine, gamma-methyl-1H-imidazole-1-propanamine,1H-imidazole-1-hexanamine, 1H-imidazole-1-heptanamine and1H-imidazole-1-octylamine as their dihydrochloride salts are obtained.

A portion of 1H-imidazole-1-butanamine dihydrochloride was then reactedwith furoyl chloride as described in Example 1, giving the desiredproduct, m.p. 88°-90° C.

Using the same procedure, the appropriate acid chlorides were convertedto the products of Examples 29-31 listed in Table VI below.

                  TABLE VI                                                        ______________________________________                                        Ex.  Acid Chloride  Product        m.p. °C.                            ______________________________________                                        29   3-chloro-benzo[b]-                                                                           3-chloro-N--[4-(1H--                                                                         84-86                                           thiophene-2-carbonyl                                                                         imidazol-1-yl)-                                                chloride       butyl]benzo[b]thio-                                                           phene-2-carboxamide                                       30   5-chloro-thiophene-                                                                          5-chloro-N--[4-(1H--                                                                         144-147                                         2-carbonyl chloride                                                                          imidazol-1-yl)-                                                               butyl]thiophene-2-                                                            carboxamide                                               31   2-thenoyl chloride                                                                           N--[4-(1H--imidazol-                                                                         103-106                                                        1-yl)butyl]thio-                                                              phene-2-carboxamide                                       ______________________________________                                    

EXAMPLE 32 N-[3-(4-phenyl-1H-imidazol-1-yl)propyl]-2-furanecarboxamide

A mixture of 28.8 g. of 4-phenylimidazole and 25 ml. of acrylonitrilewas heated at reflux temperature for 6 hours and then concentrated toremove the volatile material. The residue was mixed with 200 ml. ofethanol, 100 ml. of ammonium hydroxide and 6 g. of Raney Nickel catalystand reduced in a Parr hydrogenator under hydrogen pressure untilreduction was complete. The catalyst was removed by filtration and thefiltrate was concentrated to remove the solvents. The residual oil was4-phenyl-1H-imidazole-1-propanamine.

A mixture of 2.0 g. of 4-phenyl-1H-imidazole-1-propanamine, 50 ml. ofmethylenechloride and 10 ml. of 1N sodium hydroxide was stirred and 2.0ml. of 2-furoyl chloride was added. The mixture was stirred for eighteenhours, methylene chloride was added and the layers were separated. Theorganic layer was washed with water, dried over magnesium sulfate andconcentrated. The residue was washed onto a filter with diethyl ether,giving the desired product, m.p. 120°-122° C.

EXAMPLE 33 N-[3-(2-phenyl-1H-imidazol-1-yl)propyl]-2-furanecarboxamide

A mixture of 28.8 g. of 2-phenylimidazole and 25 ml. of acrylonitrilewas heated at reflux temperature for 6 hours and then concentrated toremove the volatile material. The residue was mixed with 200 ml. ofethanol, 100 ml. of ammonium hydroxide and 6 g. of Raney Nickel catalystand reduced in a Parr hydrogenator under hydrogen pressure untilreduction was complete. The catalyst was removed by filtration and thefiltrate was concentrated to remove the solvents. The residual oil was2-phenyl-1H-imidazole-1-propanamine.

A mixture of 2.0 g. of 2-phenyl-1H-imidazole-1-propanamine, 50 ml. ofmethylenechloride and 10 ml. of 1N sodium hydroxide was stirred and 2.0ml. of 2-furoyl chloride was added. The mixture was stirred for eighteenhours, methylene chloride was added and the layers were separated. Theorganic layer was washed with water, dried over magnesium sulfate andconcentrated. The desired product was obtained as an oil.

EXAMPLE 34 N-Benzyl-N-[3-(1H-imidazol-1-yl)propyl]-2-thiophenecarboxamide

A mixture of 4.7 g. of N-[3-(1H-imidazol-1-yl)propyl]-2-thiophenecarboxamide, 40 ml. of dimethylformamide, and 0.96 g. of 50% sodiumhydride in oil was stirred for 2 hours and 2.62 g. of benzyl bromide wasadded. The mixture was stirred for 24 hours, concentrated to remove thedimethyl formamide, diluted with water and methylene chloride, and thelayers separated. The organic layer was washed with water, dried overmagnesium sulfate, and concentrated. The oil was twice washed withhexane and again concentrated. The desired product was obtained as anoil.

EXAMPLE 35 N-Ethyl-N-[3-(1H-imidazol-1-yl)propyl]-2-thiophenecarboxamide

The above compound is obtained when ethyl bromide is substituted forbenzyl bromide in the procedure of Example 34.

EXAMPLE 36 5-Chloro-N-[5-(1H-imidazol-1-yl)pentyl]-2-thiophenecarboxamide

A solution of 1.8 g. of 5-chlorothiophene-2-carbonyl chloride in 10 ml.of CH₂ Cl₂ was added to a mixture of 1.52 g. of1H-imidazole-1-pentanamine, 10 ml. of 1N NaOH and 50 ml. of CH₂ Cl₂. Thereaction mixture was stirred for 20 hours and then treated with 25 ml.of CH₂ Cl₂ and 5 ml. of 1N NaOH. The layers were separated and theorganic layer was washed with water, dried over MgSO₄ and concentrated.The crystalline residue was washed with diethyl ether whereby thedesired product, m.p. 123°-125° C., was obtained.

EXAMPLE 37 5-Chloro-N-[6-(1H-imidazol-1-yl)hexyl]-2-thiophenecarboxamide

The title compound, m.p. 96°-98° C., was obtained when5-chlorothiophene-2-carbonyl chloride was reacted with1H-imidazole-1-hexanamine by the procedure of Example 36.

EXAMPLE 38 5-Chloro-N-[8-(1H-imidazol-1-yl)octyl]-2-thiophenecarboxamide

When 1H-imidazole-1-octylamine is treated with5-chlorothiophene-2-carbonyl chloride by the procedure of Example 36,the title compound, m.p. 95°-97° C., was obtained.

EXAMPLE 39 5-Chloro-N-[3-(1H-imidazol-1-yl)butyl]-2-thiophenecarboxamide

When gamma-methyl-1H-imidazole-1-propanamine is treated with5-chlorothiophene-2-carbonyl chloride by the procedure of Example 36,the above compound, m.p. 141°-143° C., is obtained.

EXAMPLE 40 5-Chloro-N-[4-(1H-imidazol-1-yl)-2-butenyl]-2-thiophenecarboxamide

A mixture of 100 g. of 1.4-dichlorobutene, 74 g. of potassiumphthalimide and 1500 ml. of dimethylformamide was stirred at roomtemperature for 24 hours. The reaction mixture was concentrated toremove the solvent and residue taken up with 2000 ml. of boiling hexaneand again concentrated. The residue was dissolved in methylene chloride,washed with water, dried over magnesium sulfate and concentrated toobtain 46 g. of N-(4-chloro-2-butenyl)isoindole-1,3(2H)-dione, m.p.79°-81° C.

A mixture of 23.5 g. of N-(4-chloro-2-butenyl)-isoindole-1,3(2H)-dione,11.0 g. of sodium imidazole and 200 ml. of dimethyl formamide was heatedon the steam bath for 18 hours and concentrated to remove the solvent;the residue was taken up in methylene chloride, washed with water, driedwith magnesium sulfate and again concentrated. The residue was dissolvedin hot ethylacetate and allowed to cool andN-[4-(1H-imidazol-1-yl)-2-butenyl]isoindole-1,3-(2H)-dione, m.p.106°-108° C., was obtained.

A mixture of 26.8 g. ofN-[4-(1H-imidazol-1-yl)-2-butenyl]isoindole-1,3-(2H)-dione, 4.85 ml ofhydrazine hydrate and 250 ml. of ethanol was heated at refluxtemperature for 6 hours. The mixture was cooled and 225 ml. of 3Nhydrochloric acid was added and the mixture was again heated at refluxtemperature for 3 hours. The precipitate was filtered off and the motherliquor was concentrated once more and then treated with saturatedpotassium carbonate solution. Extraction with methylene chlorideresulted in 4-(1H-imidizol-1-yl)-2-butenamine, obtained as an oil.

A solution of 1.65 g. of 4-(1H-imidazol-1-yl)-2-butenamine, 60 ml. ofmethylene chloride and 12 ml. of 1N sodium hydroxide was stirred and 1.8g. of 5-chlorothiophen-2-carbonyl chloride was added. The reactionmixture was stirred for 18 hours, 40 ml. of methylene chloride and 5 ml.of 1N sodium hydroxide was added and the layers were separated. Theorganic layer was washed with water, dried over magnesium sulfate andconcentrated and the desire compound was obtained, m.p. 115°-117° C.

We claim:
 1. A compound selected from the group consisting of those ofthe formula: ##STR8## wherein A is a divalent moiety of the formulae:

    --C.sub.n H.sub.2n -- or --CH.sub.2 CH═CHCH.sub.2 --

wherein n is an integer from 2 to 8, inclusive; R₁ is hydrogen, alkyl(C₁ -C₃) or benzyl; R₂ and R₃ are each hydrogen, alkyl(C₁ -C₃) orphenyl, Q is a divalent moiety of the formulae: ##STR9## wherein m iszero, 1, 2 or 3; and HET is a heterocyclic moiety of the formulae:##STR10## wherein Y is oxo or thio; R₄ is hydrogen, halogen, dihalogen,lower alkyl or nitro; and R₅ is hydrogen or halogen; and thepharmacologically acceptable acid-addition salts thereof.
 2. Thecompound according to claim 1;N-[3-(1H-imidazol-1-yl)propyl]-2-furanecarboxamide.
 3. The compoundaccording to claim 1;5-chloro-N-[4-(1H-imidazol-1-yl)butyl]-2-thiophenecarboxamide.
 4. Thecompound according to claim 1;N-[3-(1H-imidazol-1yl)propyl]-5-nitro-2-furanecarboxamide.
 5. Thecompound according to claim 1;N-[3-(1H-imidazol-1-yl)propyl]-α-oxo-thiophene acetamide.
 6. Thecompound according to claim 1;3-chloro-N-[2-(1H-imidazol-1-yl)ethyl]-2-benzo[b]thiophenecarboxamide.7. The compound according to claim 1;N-[4-(1H-imidazol-1-yl)butyl]-2-thiophenecarboxamide.
 8. The compoundaccording to claim 1;5-chloro-N-[3-(1H-imidazol-1-yl)propyl]-2-thiophenecarboxamide.
 9. Thecompound according to claim 1;3-chloro-N-[3-(1H-imidazol-1-yl)propyl]-2-benzo[b]thiophenecarboxamide.10. The compound according to claim 1;4,5-dibromo-N-[3-(1H-imidazol-1-yl)propyl]-2-thiophenecarboxamide. 11.The compound according to claim 1;5-chloro-N-[3-(1H-imidazol-1-yl)propyl]-2-benzo[b]thiophenecarboxamide.12. The method of inhibiting thromboxane synthetase enzyme in a mammalwhich comprises administering internally to said mammal an effectivethromboxane synthetase enzyme inhibiting amount of a compound ofclaim
 1. 13. A thromboxane synthetase enzyme inhibiting composition ofmatter in dosage unit form comprising from about 10 mg. to about 700 mg.of a compound of claim 1 in association with a pharmaceutical carrier.